Roles, Mechanisms, and Opportunities of Heat Shock Protein gp96/grp94 in Infections and Inflammation-Associated Malignancies

Chapter

Abstract

Heat shock proteins (HSP) gp96 (grp94) play an important role in modulating innate and T cell immunity via interaction with toll-like receptors (TLRs) and chaperoning antigenic peptides for antigen presentation to MHC molecules. These immunological properties of gp96 have inspired development of gp96-based prophylactic and therapeutic vaccines against various pathogens, including influenza virus, human papillomavirus, Mycobacterium tuberculosis, hepatitis B virus, and herpes simplex virus in mice models. Besides the already known underlying counterback mechanisms, the intrinsic characteristic of gp96 that simultaneously induce both effector T cell response and regulatory T cells (Tregs) may account for the modest efficiency of gp96-based immunotherapy against chronic infections and cancer. There is thus a strong need for identifying novel combination strategies (e.g., Treg inhibition, and immune checkpoint targeting) for designing a more effective gp96-based vaccine against pathogen infections. In addition, targeting cell membrane gp96 might provide a novel therapeutic approach as certain pathogens induce translocation of endoplasmic reticulum-resided gp96 to cell surface. Placenta-derived gp96 has the ability to initiate antitumor T-cell immunity via association with multiple embryo-cancer antigens against chronic infection-associated cancers. Further understanding of the placental gp96 associated-carcinoembryonic antigen repertoires that orchestrate immune defense networks against pathogen-induced cancer formation may allow ample opportunities to provide an effective strategy in cancer prevention and therapy.

Keywords

Heat shock protein gp96 T cell immunity Toll-like receptors Treg Vaccine Adjuvant Immunotherapy 

Abbreviations

ALT

Alanine aminotransaminase

APC

Antigen-presenting cell

BCG

Bacillus Calmette-Guerin

Con A

Concanavalin A

CTL

Cytotoxic T lymphocyte

CTLA4

Cytotoxic T lymphocyte-associated antigen-4

DC

Dendritic cell

DENA

Diethylnitrosamine

Foxp3

Forkhead/winged helix transcription factor

hbcag

Hepatitis B core antigen

hbsag

Hepatitis B surface antigen

HBV

Hepatitis B virus

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

HPV

Human papillomavirus

HSP

Heat shock protein

HSV

Herpes simplex virus

IL

Interleukin

LPS

Lipopolysaccharide

mab

Monoclonal antibody

MHC

Major histocompatibility complex

MDP

Muramyl dipeptide

MAPK

Mitogen-activated protein kinase

NLRP3

NLR family, pyrin domain containing 3

PD-1

Programmed death-1

PD-L1

Programmed death 1 ligand 1

TAP

Transporter associated with antigen processing

TB

Tuberculosis

TLR

Toll like receptor

TNF

Tumor necrosis factor

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Key Laboratory of Pathogenic Microbiology and Immunology, Institute of MicrobiologyChinese Academy of SciencesBeijingChina
  2. 2.Hollings Cancer Center, Department of Microbiology and ImmunologyMedical University of South CarolinaCharlestonUSA

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